beta-aminoacylphenoxy-and beta-aminoacylphenylmercapto-derivatives of monocarboxylicacids



United States Patent 13 AMJNOACYLPHENOXY- AND ,3 AMINOACYL-PHENYLMERCAPTO-DERIVATIVES OF MONO- CARBOXYLIC ACIDS Everett M. Schultz,51 Meade Road, Broad Axe Village, Ambler, Pa., and James M. Sprague,Plymouth Road, Gwynedd Valley, Pa. No Drawing. Filed Nov. 13, 1962, Ser.No. 237,288

34 Claims. (Cl. 260- -294) This application is a continuation-in-part ofUS. patent application Serial No. 155,961, filed December 6, 1961, andof Serial No. 83,635, now abandoned, filed January 19, 1961, of whichsaid application No. 155,961 also is a continuation-in-part.

This invention is concerned with B-amino-acylphenyl compounds in whichsaid phenyl ring is further linked to an organic carboxylic acid moietythrough oxygen or sulfur and in which the said phenyl ring has n furthersubstituents, n being a whole number from zero to four, as well as thesalts, esters and amides thereof. More particularly the invention isconcerned with salts of a-(aminomethyl)acylphenyl compounds wherein saidorganic carboxylic acid moiety is selected from an alkanoic acid or anaromatic carboxylic acid having a sixmembered ring such as benzoic acidor a phenyl alkanoic acid.

A more specific embodiment of the invention is concerned withfi-aminoacylphenoxyand B-aminoacylphenylmercapto derivatives ofmonocarboxylic acids wherein the monocarboxylic acid portion thereof isderived-from an aliphatic-, aliphatic-aromatic-, or anaromatic-monocarboxylic acid. These compounds can be illustrated by thestructural formula:

wherein:

the substituent ICC aryl or aryl-oxy, especially a phenyl or phenoxywherein the aryl-(phenyl) moiety can be unsubstituted or a substituentcan be attached, e.g., a lower alkyl, halogen or lower alkoxy Isubstituent; R R R and R respectively can represent the same ordiiferent group selected from hydrogen, halogen or halogen-like, loweraliphatic straight or branched chain, lower aliphatic-oxy or loweraliphatic-thio straight or branched chain, unsubstituted or having asubstituent,

such as a carboxy substituent, hydroxy, attached at the 2- or 6-position nitro, amino, especially an acylamino as acetylamino, aryl,especially phenyl,

unsubstituted or substituted, e.g. having a halogen or lower alkylsubstituent, or wherein R and R and/or R and R can additionally belinked together to form, with the ring carbons to which they areattached, a 5- or 6-membered carbocyclic ring; A represents oxygen orsulfur B represents a divalent I aliphatic,

aromatic, preferably a phenyl group, or aliphatic-aromatic group,preferably a phenyl-lower alkyl; X represents hydroxyl, alkoxyl,

unsubstituted or substituted, the substituent(s) being di-aliphaticamino and the like, amino,

such as an amino group of the structure -NR' R wherein R andR are thesame or dilferent' group or aromatic, unsubstituted or substitutedgroup, especially substituted phenyl, or R and R can be joined togetherto form, with the nitrogen atom to which they are attached, a ringcontaining one or more hetero atoms as morpholino, piperazinyl,l-pyrrolidinyl, piperidino, and the like, I hydrazine preferablysubstituted, advantageously a 2,2-

di-lower alkyl hydrazine, Y and Y respectively can represent the'same ordifferent group selected from lower alkyl, e.g., methyl and the like, orY and-Y can be joined together e'itherdirectly or through a hetero atom,to form with the nitrogen atom to which they are attached a heterocyclicring such as piperidino, and the like.

aliphatic, unsubstituted or substituted,

In the above definitions and in the claims, the term halogen embraceshalogen-like groups and represents chlorine, bromine, iodine, fluorine,halomethyl especially trichloromethyl, trifluoromethyl and the like.Also in the above definitions and in the claims, the term amino shouldbe understood to embrace primary, secondary, tertiary and quaternaryamino groups and the like, as well as the usual pharmaceuticallyacceptable salts thereof.

The fl-acylphenoxyor the ,B-acylphenylmercaptocompounds or the saltsthereof having the structure illustrated above possess diuretic,natriuretic and chloruretic properties and are therefore useful in thetreatment of many ailments resulting from an excessive retention ofwater and/or electrolytes especially sodium, chloride or sodium andchloride ions, as in the treatment of edema and other conditionsassociated with electrolyte and fluid retention.

The compounds of this invention are prepared by the reaction illustratedbelow:

YY NH (wherein Y and Y have the meaning hereinbefore assigned) in thepresence of formaldehyde or paraformaldehyde. The reaction can becarried out either with or without a solvent. Thus, the reactants can beadmixed and heated to effect the reaction or the reaction can be carriedout in an aqueous medium or in the presence of an organic solventespecially methanol, ethanol or other alcohol. Various salts can beformed by preforming the salts of the amine reactant with the selectedacid. Preferred salts are formed with hydrohalides especially thehydrochlorides and hydrobromides.

Compounds of this invention wherein X represents an amide, hydrazide oran alkoxy group can be prepared by known methods by initially convertingthe product VIII to its acid chloride, and then reacting the acidchloride with the desired amine, hydrazine or alcohol to form the amide,hydrazide or ester derivative of product VIII.

While, for the sake of simplicity, the above reaction scheme illustratesthe preparation of p-(fl-aminoacyD- phenoxyacetic acids, it is to beunderstood that the re- R R 0 I I action scheme and the above describedreaction can be I] I YY NH-HCI h d h l g ,c used to prepare t e or erpos1t1on 1somers an t at it a so I 01110 illustrates a method forpreparing other B-aminoacyl- 5 phenyl compounds wherein said phenyl ringis linked to VII an organic carboxylic acid moiety through oxygen orsulfur, as well as the salts, esters and amides thereof. R3 R4 I IPREPARATION OF SATURATED-ACYLPHENOXY- R=-C HC I 0cHlc 0,11 ACETIC ACIDSv11 YY N-dH; The intermediate saturated-acylphenoxyactic acid R5 (VIIgenerally can be made by one of two methods H01 VIII from the knownphenols (I), as illustrated by the following reaction scheme.

PREPARATION OF SATURATED-ACYLPHENOXYACETIC ACIDS (VII) a 34 Rs R4 1i}:1?;

I I I CH 8 Ii -CH 0 001 1 OH M -oc1n mom-iz- OCHa I I NaOH 4 A101: R5TIN 1'2 in Ra e I II III lClCHzC 01H l A101:

NaOH R R R R R3 R4 I .I 0 I Na 0 I I II a t) II -OCH1O 02H R*'CH:C--OCH:CO:EI7 R'-CH:-G OH BrCHzCOzEt I 1'1: 1'15 1 1 1 1 Ra Ra VI V IV n0 H1O lNaOH c1crr,o 02H A1011 NaO R R 5] Ii -C H1--C O CHzC 01H VII The(fl-aminoacyl)phenoxyacetic acid compounds of the invention (VIII)advantageously are prepared by reacting the saturated acyl compound(VII) or its ester One method illustrated above involves heating thephenol (I) with an excess of chloroacetic acid in the presence of atleast two moles of an alkali metal hydroxide with a salt of a secondaryamine having the formula to form the phenoxyacetic acid (VI).

The phenoxyacetic acids (VI) then are converted to the saturatedacylphenoxyacetic acids (VII) by the Friedel-Crafts reaction involvingan acyl halide,

R CH COCI and Compound VI in the presence of aluminum chloride. Thereaction can be carried out either with or without a solvent, such ascarbon disulfide. Product VII can be converted to an ester by reactionwith an alcohol in the usual manner. As mentioned above, the esters canbe converted to the (B-aminoacyl)phenoxyaliphatic acid ester compound.

The above procedure which describes the preparation ofacylphenoxyaliphatic acids generally can be adapted to prepare theacylphenylrnercaptoaliphatic acids as well.

Although this method has limited applicability, it is the one of choice,where applicable, since it is the most direct route.

A second method although longer, has a broader utility. In this process,the phenol (I) is converted to the corresponding anisole (II) (orphenetole) by known methods, as by reaction with dimethyl sulfate ordiethyl sulfate in the presence of a base such as sodium or potassiumhydroxide. The anisole (II) (or phenetole) then is reacted With the acylhalide, R CH COCl, in the presence of anhydrous aluminum chloride and asolvent as ligroin.

or carbon disulfide. The acylanisole (III) (or -phenetole) then isconverted to the corresponding acylphenol (IV) by subsequent treatmentwith additional aluminum chloride in a solvent such as heptane.

The acylphenol (IV) canthen be converted to the acylphenoxyacetic acid(VII) by reaction with a haloaliphatic acid (preferably chloroaceticacid) in the presence of sodium or potassium hydroxide.

Alternatively, Compound VII can be prepared from Compound IV by a twostep process whereby the acylphenol (IV) is treated with. a suspensionof sodium hydride in ethylene glycol dimethyl ether (glyme) (or sodiumethoxide in ethanol) followed by reaction with a haloaliphatic acidester, as ethyl bromoacetate, to form an acylphenoxyacetic acid ester(V). Hydrolysis of the ester V by aqueous or alcoholic base producesCompound VII.

While, for simplicitys sake, the reaction scheme illustrating thepreparation of the acylphenoxyacetic acids (VII) shows the preparationof para-acylphenoxyacetic acid compounds, the methods illustrated anddescribed above can be employed to make the other position isomers also.It sometimes is more convenient, however, to prepare the ortho isomersby the Fries Rearrangement illustrated below. The Rs in the followingstructures are attached to the phenyl nucleus so as to leave one of theortho positions unsubstituted.

PREPARATION OF O-A%III,P)HENOXYACETIC ACIDS R R R R 1 R HzCOCl H I I--OH I I -O-C-CH:R R R R5 1 I XII A101: A

' (Fries Rearraugement) NaH (or N 2.0 E t) BIC HaCOnEt R B C OCHzR VaIVa ig g /C ICH2C 02H 2 NaOH R3 R4 ooomm VIIa According to the FriesRearrangement procedure illustrated above, the phenol (I) initially isesterified by reaction with the acyl halide, R CH COCl, to form thecorresponding phenolic ester (XII) which is rearranged to theortho-acylphenol (IVa), upon heating with aluminum chloride. Theconversion of the ortho-acylphenol (Net) to the desiredortho-acylphenoxyacetic acid (VIIa').

by either (a) Treatment with chloroacetic acid in presence of base (b)Reaction of IVa with sodium hydride or sodium alkoxide followed byreaction with a. haloacetic acid ester to form Va which is hydrolyzed toVIIa invention to the particular methods or the particular compoundsspecifically described.

The following examples illustrate various methods by which theacylphenol starting substances can be prepared. The complete examplestaken in conjunction with Table I describe the preparation and providethe physical constants of all acylphenols used in the synthesis of thenovel compounds of this invention that were not described in theavailable literature.

Example 1 illustrates the preparation of an acylphenol (IV).from ananisole (II).

. Example 1.2',3-dichl0r0-4-hydr0xy-1-cycl0- pentaneacetophenone To amixture of 2,3-dichloroanisole (38.8 g., 0.213 mole) andcyclopentaneacetyl chloride (25 g., 0.17 mole) in carbon disulfide (250ml.), there is added, with stirring, aluminum chloride (46.6 g-., 0.35mole). Themixture then is heated at 50-60 C. for 5 hours. The car'- bondisulfide then is removed by distillation, heptane (200 m1.) andaluminum chloride (26.67 g., 0.2 mole) is added and the mixture stirredand heated on the steam bath for 2 hours. The solvent then is decantedand ice water (400 ml.) is added slowly with external cooling in an icebath. This is followed by addition of concentrated hydrochloric acid (40m1.), and extraction with ether. The ether extract is washed With waterand the ether then evaporated.

- The residue is added to 10% sodium hydroxide solution ml.) and themixture heated on a steam bath for 3 hours to saponify any ester thatmay have been formed. After acidification with hydrochloric acid,2',3'-dich1oro- 4'-hydroxy-1-cyclopentaneacetophenone is obtained, M.P.86-88 C., 28 g. yield. After recrystallization from a mixture ofisopropyl alcohol and water and an additional recrystallization fromcyclohexane, the product melts at 87-88 C.

Analysis.Calculated for C H CI O C, 57.16; H, 5.17; Cl, 25.96. Found: C,57.77; H, 5.10; Cl, 25.80.

Example 2 illustrates a method by which the phenolic esters (XII), usedin the Fries Rearrangement can be prepared from a phenol, I. Y

7 Example 2.3-clzl0r0plzenyl propz'onate 3-chlorophenol (1.11 mole) isadded gradually to propionyl chloride (101.5 g., 1.1 mole) and themixture then heated 'on the steam bath for one hour and distilled togive 3-chlorophenyl propionate, B.P. 122.5 C. at 16 mm. pressure, N1.5105.

Analysis.Calculated for C H CIO C, 8.55 H, 4.91; Cl, 19.20. Found: C,58.79; H, 5.00; Cl, 19.26.

The following Examples 3-5 illustrate the Fries Rearrangement ofCompound XII to Compound lVa; the process of Example 3 being carried outat 140 C. and that of Examples 4 and 5 being carried out at between90100 C.

Example 3.2-pr0pi0nyl-5-chlorophenol 3-chlorophenyl propionate, fromExample 2 (147 g., 0.8 mole), is placed in a l-liter'round flask andanhydrous aluminum chloride (128 g., 0.96 mole) is added slowly withstirring and cooling at 30-40" C. The flask then is plunged into a metalbath at 1,40 C. and kept at this temperature for minutes. The flask thenis cooled slowly while rotating slowly. Benzene (150 ml.) then is addedand the aluminum complex is decomposed by the careful addition of 3 Nhydrochloric acid with cooling. The benzene is separated and washed with3 N hydrochloric acid and with water and the benzene then evaporated andthe residue taken up in ether and extracted with 500 ml. of 5% sodiumhydroxide in several portions. The aqueous extract. is acidified with 12N hydrochloric acid, and the oil that separates is extracted with etherand the ether solution dried over sodium sulfate. The ether then isevaporated and the residue distilled to give 2-propionyl-5-chlorophenol,B.P. 130-l40 C. at 60 mm. pressure, M.P. 4547 0, yield 78.5 g.

Analysis.Calculated for C H CIO C, 58.55; H, 4.91 Cl, 19.21. Found: C,58.50; H, 5.12; Cl, 19.08.

Example 4.-2-butyryl-3,5-dimetlzylplzenol To a solution of 0.15 mole of3,5dimethylphenol in 60 ml. of pyridine is added during 15 minutes 0.18mole of butyryl chloride with ice bath cooling. The mixture is permittedto stand 1 hour at room temperature, then diluted with 300 ml. of waterto give an oily product which is taken up in ether. The ether solutionis washed thoroughly with dilute acid and water, dried, and the etherevaporated to leave the butyric acid ester of 3,5- dimethylphenol. Theether is mixed with 0.29 mole of aluminum chloride and then heated 1.6hours on the steam bath. The reaction mixture is poured onto ice and thesolid product obtained is recrystallized from cyclohexane to give2-butyryl-3,S-dimethylphenol, M.P. 57- 58.5 C.

Analysis.Calculated for C H O t C, 74.97; H, 8.39. Found: C, 74.63; H,8.35.

Example 5.2-bu1yryl-3,5-rlichloroplzenol This product is preparedfollowing substantially the same procedure described in Example 4employing 24.4 g. (0.15 mole) of 3,5-dichlorophenol and 19.3 g. (0.18mole) of butyryl chloride. This procedure gives 33.2 g. of the liquidbutyric acid ester of 3,5-dichlorophenol and 21.5 g. of2-butyryl-3,S-dichlorophenol which after recrystallization from ligroinmelts at 45-48" C. A further recrystallization from the same solventgives the product with a M.P. of 47-485 C.

Analysis.-Calculated for C H Cl O C, 51.52; H, 4.32. Found: C, 52.37; H,4.35.

Examples 69 describe other methods, not illustrated in the abovereaction schemes, which can be used to prepare acylphenols.

Examples 6 and 7 specifically illustrate the conversion of benzaldehydeto form an acylphenol.

Step A: Preparation of 2, 6-dichlor0-3-metlzoxy-oi-propylbenzylalcoh0l.2,6-dichl0ro-3-methoxybenzaldehyde (109 g., 0.53 mole) is addedduring 0.5 hour to a solution of propylmagnesium bromide in 600 ml. ofether prepared from 72.4 g. (0.59 mole) of propyl bromide and 14.4 g.(0.59 mole) of magnesium. The mixture is refluxed 1.5 hours and thenpoured into ice-cold dilute hydrochloric acid. The ether layer isseparated, washed with water and dried over sodium sulfate. Evaporationof the ether gives 126 g. of 2,6-dichloro-3-methoxy-u-propylbenzylalcohol as a yellowish oil.

Step B: Preparation of 2,6-dichl0ro-3-metho xybutyrophen0ne.A solutionof 126 g. (0.51 mole) of 2,6- dichloro-3-methoxy-a-propylbenzyl alcohol,and 98.5 g. (0.33 mole) of sodium dichromate dihydrate in 150 ml. ofwater and 400 ml. of acetic acid is heated 1 hour on the steam bath. Thesolution is diluted with 2.5 liters of water to produce an oily productwhich is taken up in ether, the ether solution washed with water, andsodium bicarbonate solution, and then dried over sodium sulfate.Evaporation of the ether gives 119 g. of 2,6-dichloro3-methoxybutyrophenone as a yellow oil.

Step C: Preparation of 2',6-dichl0r0-3-hydr0xybntyrophen0ne.A mixture of119 g. (0.48 mole) of 2,6'-dichloro-3'-methoxybutyrophenone and 191 g.(1.44 mole) of aluminum chloride in 600 ml. of heptane is stirred andheated 2.5 hours on the steam bath. The heptane then is decanted fromthe viscous precipitate which is hydrolyzed by the addition of ice anddilute hydrochloric acid. The oily product obtained is taken up in etherand purified by distillation yielding 76.5 g. of2',6'-dichloro-3'-hydroxybutyrophenone, B.P. 148l50/1.5 mm., N 1.5558.

Analysis.-Calct1lated for C H Cl O C, 51.52; H, 4.32. Found: C, 51.67;H, 4.57.

Example 7.2'-clzlore-3'-hydr0xybutyrophenone Step A: Preparation of2-clzloro-3-methoxy-a-propylbenzyl alc0h0l.By following substantiallythe same procedure described in Step A, Example 6, but replacing the2,6-dichloro-3-methoxybenzaldehyde by an equimolecular quantity of2-chloro-3-methoxybenzaldehyde, and following substantially the sameprocedure described in Step A of Example 6, there is obtained a 97%yield of 2-chloro- 3-methoxy-a-propylbenzyl alcohol.

Step B: Preparation of 2-chZora-3-metlzoxybutyrophenone.-By followingsubstantially the same procedure described in StepB of Example 6 butreplacing the 2,6- dichloro-3-methoxy-/8-propylbenzyl alcohol by anequimoleoular quantity of 2-chloro-3-methoxy-a-propylbenzyl alcohol, andfollowing substantially the same procedure described in Step B ofExample 6 there is obtained 2- chloro-3'-methoxybutyrophenone, B.P.174-180 C. at 22 mm. pressure N 1.5375.

Step C: Preparation of 2-clzl0r0-3'-hydroxybutyrophenone.By replacingthe 2',6'-dichloro-3-methoxybutyrophenone employed in Step C of Example6 by an equimolecular quantity of 2-chloro-3-methoxybutyrophenone andfollowing substantially the same procedure described in Step C ofExample 6 there is obtained 2- chloro-3'-hydroxybutyrophenone, B.P. 120C. at 0.3 mm. pressure, yield 88%.

Analysis-Calculated for C H CIO C, 60.46; H, 5.58. Found: C, 59.90; H,5.54.

Example 8 illustrates a method by which a phenyl Grignard can beconverted to an acylphenol.

Example 8.-2-(Z-meilzylenebutyryl) -3-nzethylplzenoxyacetic acid Step A:Preparation of 2'-meth0xy-6'-methylbntyrophenone.To a solution ofZ-methoxy-6-methylphenyl magnesium bromide [prepared from2bromo-3-methylanisole (16.5 g., 0.082 mole) and magnesium (2.1 g.,0.086 mole)] in 40 ml. of ether is added a solution of 9 butyronitrile(5.9 g., 0.085 mole) in ether (10 m1.) and the mixture refluxed for 2%hours. The reaction product then is poured into a mixture of ice andhydrochloric acid which then is heated 18 hours on the steam bath. Theoil that separates is taken up in ether, the ether solution dried andthe ether then evaporatedto give an 8.4 g. yield of 2-methoxy-6'-methylbutyrophenone.

Step B: Preparation of 2'-hydr0xy-6-meihylbutyroph- I Example9.-2,4-dimeIhyI-S-butyrylphenol 2,4-dimethyl--aminobutyrophenone (119.5g., 0.63 mole) in a solution of 190 ml. of sulfuric acid in 945 also isidentified in Table I.

10 are identified in Table I. Each of the compounds was made byreplacing the 2,3-dichloro-anisole employed in Example 1 by anequimolecular quantity of the anisole or phenetole I R R" (II)identified in Table I and by replacing the cyclopentaneacetyl chlorideemployed in Example I by an equimolecular quantity of the acylchloride,R CH COCl, which The reaction is carried out in substantially the samemanner as described in Example I to give the acylphenol,

R R (IV) which also is identified in the table by structure, melting orboiling point and by elemental analysis for those ml. of water isdiazotized at 5 C. with 46 g. (0.67 mole) products which were purified.

'TABLE I R R IV Ex. No.

All;

End product M.P. Analysis B PA),

Yield,

percent Empirical C C1 CH Cl Cl CH Br Cl CH:

N0 CH3 CH;

CII3CONII CII;

' Cl CH CHz C1 C1 CH C1 C1 CH 19 H Cl CH CHJCH] CH3CH OHaCHg CIIQCH:

CHgCHg (CHa)zCH iiJHriClOa: 82. 5-84 Cale Found cro io h zl as aa aa uia t Cal I ound 0 13 501 03:

Cale Found- 12 14 2 2 Oalc Found Cale F0und Cale Found a 170-204 03 mm.

of sodium nitrite. The solution of diazonium salt is heated on the steambath for 30 minutes. The phenol separates as an oil which crystallizeswhen the mixture is cooled. The product is taken up in ether, extractedinto 5% sodium hydroxide solution and reprecipitated by acidification.After recrystallization from ethanol there is obtained 76.5 g. of2,4-dimethyl-5-butyrylphenol, M.P. 95-100 C. Further recrystallizationfrom the same solvent gives the product melting at 100.5102.0 C.

Analysis.Catlculated for C H O C, 74.97; H, 8.39. Found: C, 74.41; H,8.29.

Other acylphenol (W) starting materials used inthe Example20.2,3,5,6-tetramethylphenoxyacetic acid A 500 ml., 4-necked, roundbottomed flask fitted with stirrer, condenser and two dropping funnelsis charged with 40.0 g. of 2,3,5,6-tetramethylphenol and 21.5 g. ofsodium hydroxide in 90 ml. of water. The solution preparation of thenovel compounds of this invention is heated at -95 C. on a steam bathwhile 34.5 g. of

chloroacetic acid in 35 ml. of water is slowly added. Heating iscontinued one-half hour and sodium hydroxide (21.5 g.) and chloroaceticacid (34.5 g.) are added to the reaction mixture. Heating is continuedfor an additional 40 minutes, the solution filtered, acidified withconcentrated hydrochloric acid and cooled whereupon a solid product, 45g. (82%) is formed. After recrystallization from 600 ml. of heptane,purified 2,3,5,6-tetramethylphenoxyacetic acid is obtained, M.P. ll7-118C.

Analysis.Calculated for C H O C, 69.21; H, 7.74. Found: C, 69.05; H,7.67.

Example 21 .3-(3-cl1l0r0phenylmercapto propionic acid A solution of 14.5g. (0.10 mole) of m-chlorothiophenol in 125 ml. of sodium hydroxidesolution is mixed with a solution of 15.9 g. (0.10 mole) ofS-bromopropionic acid in 150 ml. of saturated sodium bicarbonatesolution. After 4 hours the solution is acidified and the precipitatedproduct recrystallized from aqueous ethanol to give 19.6 g. of3-(3-chlorophenylmercapto)- propionic acid, M.P. 79.5-81.5 C.

Analysis-Calculated for C H CIO S: C, 49.88; H, 4.19. Found: C, 50.53;H, 4.23.

The following examples illustrate various methods by 'which thesaturated-acylphenoxyacetic acid (VII) intermediates (employed in thepreparation of the novel compounds of this invention) can be prepared.The complete examples taken in conjunction with Tables II to VI describethe preparation and provide the physical constants of allsaturated-acylphenoxyalkanoic acids andsaturated-acylphenylrnercapto-alkanoic acids employed in the synthesisof the novel compounds described herein, which products (VII) had notbeen described in the available literature.

Example 22 illustrates the use of the Friedel-Crafts reaction in thepreparation of saturated acylphenoxyacetic acids (VII) from aphenoxyacetic acid (VI).

Example 22.-3-chl0r0-4-pr0pionyIplzenoxyacetic acid Powdered aluminumchloride (216 g., 1.625 mole) and carbon disulfide (400 ml.) are placedin a 1-liter, 4-necked flask equipped with a stirrer, dropping funnel,reflux condenser and internal thermometer. 3-ch lorophenoxyacetic acid(93.29 g., 0.5 mole) is added in portions with stirring and thenpropionyl chloride (57.8 g., 0.625 mole) is added dropwise with stirringover a period of 0.5 hour at a temperature of about 22-26 C. Afterstirring 1 hour at room temperature, the reaction flask is placed in awater bath and the temperature maintained at 50 C. for 3 hours. Thecarbon disulfide then is decanted and the aluminum complex remaining isadded to a mixture of 1 kg. of ice and 125 ml. of concentratedhydrochloric acid. The solid that separates is dried in air and thendried further by azeotropic distillation with benzene and thencrystallized from benzene to give 77.5 g. (32%) of3-chloro-4-propionylphenoxyacetic acid, M.P. 107.5-109" C.

Analysis.Calculated for C I-1 C C, 54.44; H, 4.57; Cl, 14.61. Found: C,54.88; H, 4.46; Cl, 14.36.

Example 23 describes an alternate method whereby thesaturated-acylphenoxyacetic acids (VII) are prepared by the reaction ofan acylphenol (IV) with an a-bromoester in glyme in the presence ofsodium hydride to form an ester of an acylphenoxyacetic acid (V) whichthen is hydrolyzed to form the acylphenoxyacetic acid (VII).

Example 23.3-pr0pionylphenoxyacetic acid A solution of 0.1 mole of 3propionylphenol in 60 ml. of ethylene glycol dimethyl ether (glyme) isadded to a suspension of 0.1 mole of sodium hydride in 40 ml. of thesame solvent. Then 0.11 mole of ethyl bromoacetate is added during 25minutes. The mixture is refluxed 1 hour and the precipitated sodiumbromide is filtered off and solvent distilled in vacuo. To the residueis added ml. of 10% sodium hydroxide solution and the mixture heated onthe steam bath for 10 minutes until a clear solution is formed. Thesolution is acidified to precipitate the product which sooncrystallizes. Recrystallization from a mixture of benzene andcyclohexane gives 3-propionylphenoxyacetic acid, M.P. 72-78" C.

The procedure described in Example 24 illustrates a method whereby thesaturated acylphenoxyacetic acids (VII) are prepared by the reaction ofan acylphenol (IV) with an a-bromoester in an alcohol and in thepresence of sodium alkoxide to form an ester of an acylphenoxyaceticacid (V) which then is hydrolyzed to the corresponding phenoxyaceticacid (VII).

Example 24.2-(4-butyryl-3-chl0roplzcnoxy) butyric acid Sodium (4.8 g.,0.21 g. atom) is dissolved in 150 ml. of absolute alcohol to form asolution of sodium ethoxide. 2'-chloro-4'-hydroxybutyrophenone, obtainedas described in Example 10 (39.73 g., 0.20 mole) is added, the solutionheated to boiling and ethyl a-bromobutyrate (39.01 g., 0.20 mole) addeddropwise with stirring during 0.5 hour. The mixture is stirred andrefluxed for 4.5 hours and the solvents then distilled on a steam bath.To the residue sodium hydroxide (16 g., 0.4 mole) in water (150 ml.) isadded and the mixture heated with stirring for 2.25 hours. The reactionmixture then is cooled and extracted with ether and acidified withhydrochloric acid. The oil that separates is extracted with ether, thesolution dried over anhydrous sodium sulfate and the ether evaporated togive a residue which distills at between 173197 C. at 0.2 mm. pressureto give 46.5 g. (81%) of 2-(4-butyryl-3-chlorophenoxy)butyric acid.

Analysis.Calculated for C H ClO C, 59.05; H, 6.02; Cl, 12.46. Found: C,59.22; H, 6.23; Cl, 12.24.

Example 25 illustrates still another method for making the saturatedacylphenoxyacetic acids (VII) wherein an acylphenol (IV) reacts with ana-haloacid in water in the presence of sodium hydroxide to form anacylphenoxyacetic acid (VII) directly.

Example 25.2,6-dichl0r0-4-butyrylphenoxyacetic acid3',5-dichloro-4'-hydroxybutyrophenone [prepared by the FriesRearrangement of 2,6-dichlorophenylbutyrate] (51.5 g., 0.221 mole) inwater (250 m1.) is combined with a solution of sodium hydroxide (17.68g., 0.442 mole) in 35 ml. of water. To the resulting solution at 55 C.is added a solution of chloroacetic acid (20.88 g., 0.221 mole) in 21ml. of Water over a period of 30 minutes at temperature of 5557 C. withstirring. The temperature is raised to C. and the reaction solutiontreated simultaneously with a solution of chloroacetic acid (104.40 g.,1.105 mole) in ml. of water and a solution of sodium hydroxide (88.40g., 2.21 mole) in ml. of water (keeping the reaction solution slightlybasic during the entire period) over a period of 10 hours with stirring.The boiling solution is acidified with concentrated hydrochloric acid.The solid that separates after chilling in an ice bath to roomtemperature is collected, crystallized two times from a mixture ofbenzene and cyclohexane and then from benzene alone to give 25.4 g.(40%) of 2,6-dichloro-4-butyrylphenoxyacetic acid, M.P. 136 l37 C.(corn).

Analysis.-Calculated for C12H1204C12i C, H, 4.15; Cl, 24.36. Found: C,49.95; H, 4.23; Cl, 24.08.

The reaction illustrated by Example 25 also can be used to prepare theintermediate phenylacetic acid which subsequently can be acylated by themethod described in Example 22, for example, to give the saturatedacylphenoxyacetic acid (VII). The preparation of the intermediatephenylacetic acid is described in the following example.

13 Example 26.-2-chl0r0-3-methylphenoxyacetic acid The above product isprepared following substantially the same procedure described in Example25 using the following substances:

i 2-chloro-3-methylphenol 28.7 g., 0.20 mole. Chloroacetic acid 38 g.,0.40 mole. Sodium hydroxide 32 g., 0.80 mole.

other saturated acylphenoxyacetic acids (VII) by a variety of methodsnot necessarily included in the above reaction schemes.

Example 27.3-methoxy-4-butyrylphenoxyacetic acid Step A: Preparation of3-hydroxy-4-butyrylphenoxyacetic acid.'The above product was obtainedfollowing substantially the same procedure described in Example 22 usingthe following substances:

m-Methoxyphenoxyacetic acid 80.6 g., 0.4424 mole.

Carbon disulfide 500 m1. Butyryl chloride 58.71 g., 0.551 mole. Powderedaluminum chloride 191.08 g., 1.433 mole.

The above procedure yields 15.6 g. (15%) of a yellow waxy solid boilingat 197199 C. at 0.1 mm. pressure.

Redistillation gives material boiling at 203204 C. at 0.10 mm. pressure.Further recrystallization from-a mixture of benzene and cyclohexanegives -3-hydroxy-4-butyrylphenoxyacetic acid in the form of a whitecrystalline solid, M.P. 120-121 C.

Step B: Preparation of 3-methoxy-4-butyrylphenoxyacetic acid.To asolution of 3-hydroxy-4-butyrylphenoxyacetic acid 10.9 g., 0.0458 mole)dissolved in 100ml. of water containing sodium hydroxide (4.0 g., 0.1mole) is added methyl sulfate (5.78 g., 0.0458 mole) over a period of 15minutes at a temperature of 2528 C. with stirring. The temperature israised to 50 C. and the reaction solution treated simultaneously withmethyl sulfate (8.67 g., 0.0687 mole) and a solution of sodium hydroxide(6.0 g., 0.15 mole) in 35 ml. of water over a period of 45 minutes at atemperature of 50-60" C. The reaction solution then is heated underreflux with stirring for an additional two hours. The boiling reactionsolution is acidified with concentrated hydrochloric acid and the oilthat forms solidifies after cooling to room temperature. There is thusobtained 3-methoxy-4-butyrylphenoxyacetic acid, M.P. 118 132 C., yield11 g. (95%). After four recrystallizations from benzene the product isobtained in the form of white needles, M.P. 137138 C. (corn).

Analysis.Calculated for C H C, 61.89; H, 6.39. Found: C, 61.47; H, 6.42.

Example 28.-3-pr0pionyl-4-chlorophenoxyacetic acid Step A: Preparationof Z-clzl0r0-5-nitr0pr0piophen0ne.--2-chloropropiophenone (84.5 g., 0.5mole) is added to 300 ml. of fuming nitric acid (density 1.5) at atemperature of 510 C. during 18 minutes. The mixture is allowed to standat 0-5 C. for 30 minutes and then poured into ice Water. The solidproduct is recrystallized from isopropyl alcohol to give 75 g. of2-chloro-5- nitropropiophenone, M.P. 5256 C. After recrystalliza- 14tion from isopropyl alcohol, the product has a melting point of 5456 C.

Analysis.Calculated for C H ClNO C, 50.60; H, 3.77; N, 6.56. Found: C,51.47; H, 4.01; N, 6.62.

Step B: Preparation of Z-chl0r0-5-amin0propi0phenone.A solution of 25.9g. (0.121 mole) of 2-chloro-5- nitropropiophenone in 60 ml. of aceticacid is added to 240 ml. of a 7.5 N hydrochloric acid solution in whichis dissolved g. of stannous chloride dihydrate. The solution is heated 1hour on the'steam bath and then made basic by addition of sodiumhydroxide solution. The

oily product is taken up in ether, the ether then evaporatedto give ayellow oil weighing 18 g. Upon distillation the product has a boilingpoint of 143-146 C. at 0.5 mm. pressure.

Analysis.Calculated for C H ClNO: C, 58.86; H, 5.49; N, 7.63. Found: C,59.10; H, 5.58; N, 7.54.

Step C: Preparation of 3-pr0pionyl-4-chlorophen0l.2-chloro-S-aminopropiophenone (48.5 g., 0.26 mole) is dissolved in 192ml. of water and 26 ml. of concentrated sulfuric acid and diazotizedwith a solution of 17.9 g.-

(0.26 mole) of sodium nitrite in 40 ml. of water.' The diazonium mixtureis added dropwise during 30 minutes to a stirred mixtureof 340 ml. of 1N sulfuric acid containing 48 g. of cupric sulfate pentahydrate and 250ml. of toluene. The toluene layer then is separated and extracted with a5% solution of sodium hydroxide. Acidification precipitates an oilyproduct which is purified by distillation to give 13.0 g. of3-propionyl-4-chlorophenol, B.P. 140 C. at 0.5 mm. pressure.

Step D: Preparation of 3-propionyl-4-chlorophenoxyacetic acid.-3propionyl-4-chlorophenol is alkylated with ethylbromoacetate bysubstantially the same procedure described in Example 23 to give3-propionyl-4-chlorophenoxyacetic acid, M.P. 77.580.5 C.

Example 29.-3-(2,4-dimethyl-5-butyrylphenoxy)- propionic acid2,4dimethyl-5-butyrylphenol (46 g., 0.24 mole) is dissolved in 250 m1.of 10% sodium hydroxide solution. The solution is heated to boiling and180 g. (2.4 mole) of B-propiolactone is added dropwise at such a rate tokeep the solution boiling. During the addition a 10% Example30.3-chloro-4-acetylphenoxyacetic acid The above product is obtained byfollowing substantially the same method described in Example 22 usingthe ingredients listed below:

3-chlorophenoxyacetic acid 17.06 g., 0.1 mole. Acetyl chloride 7.85 g.,0.125 mole. Powdered aluminum chloride 43.5 g., 0.325 mole. Carbondisulfide ml.

The product obtained is reprecipitated from a sodium bicarbonatesolution by acidification from hydrochloric acid to give a white solidwhich, when crystallized from benzene, gives 4.94 g. of3-chloro-4-acetylphenoxyacetic acid,

Analysis.--Calculated for c ,,rr,c1o,= c, 52.53; H, 3.97; or, 15.51.Found: 0, 52.29; H, 4.35; 01, 15.24.

1 5 Example 31-.--3-clilor0-4-(3-plzenylpropi0nyl)phenoxyacetic acidStep A: Preparation of 3-chlor0-4-(3-plzenylacryl0yl)- plzenoxyaceticacid.-3-chloro-4-acety1phenoxyacetic acid prepared as described inExample 30 (4.4 g., 0.0193 mole) and benzaldehyde (2.1 g., 0.0193 mole)is dissolved in a mixture of sodium hydroxide (1.8 g., 0.045 mole) in160 ml. of water and ml. of ethanol. The solution is kept at 30 C. for16 hours, acidified and the solid that separates is collected, dried at65 C. and crystallized from benzene to. give 1.2 g. of3-chloro-4-(3-phenylacryloyl)- phenoxyacetic acid, M.P. 139l40 C.

Analysis.Calculated for C H ClO C, 64.47; H, 4.13; CI, 11.19. Found: C,64.09; H, 3.99; CI, 10.97.

Step B: Preparation of 3-chloro-4-(3-phenylpropionyl)- phenoxyaceticacid.3-chloro-4-(3 phenylacryloyl)phenoxyacetic acid (24.2 g., 0.076mole) is dissolved in isopropanol (275 ml.) and hydrogenated in thepresence of 5% palladium on charcoal at 26 C. and 756 mm. pressure. Whenthe required amount of hydrogen is absorbed, the solution is warmed andfiltered to remove the catalyst and the alcohol then removed byevaporation. The product obtained is crystallized from benzene to give14.4 g. (59.3%) of 3-chloro-4-(3-phenylpropionyl)phenoxyacetic acid,M.P. 113115 C.

Analysis.Calculated for C I-1 C10 C, 64.04; H, 4.74; Cl, 11.13. Found:C, 64.28; H, 4.82; Cl, 11.11.

E vample 31-A .3-cl1lor0-4- [3-(4 clzl0r0pl1enyl)pr0pionyl]plzenoxyacetic acid Step A: Preparation of 3-clzl0r0-4-[3-(4-clzlor0plzenyl)- aezyloyl]plzenoxyacetic acid.The above compoundis prepared following essentially the method described in Example 31,Step A, using an equimolar amount of 4- chlorobenzaldehyde in place ofthe benzaldehyde used in that example to give3-chloro-4-[3-(4-chlorophenyl)- acryloyl] phenoxyacetic acid.

Step B: Preparation of 3-clzlor0-4-[3-(4-chlor0plzenyl)-propionyl]phenoxyacetic acid.-The compound obtained in Step A isconverted to 3-chloro-4-[3-(4-chlorophenyl)- propionylJphenoxyaceticacid by following essentially the same process described in Example 31,Step B.

Example 3I-B.3-ch l0ro-4-[3- (4-propylphenyl) propionyl] phenoxyaceticacid Step A: Preparation of 3-chl0ro-4-[3-(4-propylplzenyl)-acryloyl]phenoxyacetic acid. The above compound is prepared followingessentially the same method described in Example 31, Step A, using anequimolar amount of 4- propylbenzaldehyde in place of the benzaldehydeused in that example to give 3-chloro-4-[3-(4-propylphenyl)-acryloyl]phenoxyacetic acid.

Step B: Preparation of 3-clzl0ro-4-[3-(4-pr0pylplzenyl)-propionyl]phenoxyacetic acid.The compound prepared in Step A ishydrogenated in essentially the same manner as described in Example 31,Step B, to give 3-chloro-4-[3- 4-propylphenyl) propionyl] phenoxyaceticacid.

Example 31-C.3-clzlor0-4-[3-(4-metlzoxyphenyl)propionyl] phenaxyaceticacid Step A: Preparation of 3-chI0r0-4- [3-(4-metlzylphenyl)-acryloyl]plzenoxyacetic acid.The above compound is prepared by followingessentially the method described in Example 31, Step A, using anequimolar amount of 4- methoxybenzaldehyde in place of the benzaledhydeused in that example to give 3-chloro-4-[3-(4-methoxyphenyl)- acryloyl}phenoxyacetic acid.

Step B: Preparation of 3-cl1lor0-4-[3-(4-nzetlz0xyplienyl)pr0pi0nyl]plzenoxyacetic acid.Thc compound ob- 1 6 tained in Step A isconverted to 3-chloro-4-[3-(4-methoxyphenyl)propionyl]phenoxyacetic acidfollowing essentially the same process described in Example 31, Step B.

Example 32 .-3 -metllyl-4 4 -clzl orob utyryl plze/zoxyacetic acid Theabove product is obtained following substantially the same methoddescribed in Example 22, using the following substances:

3-methylphenoxyacetic acid 33.2 g., 0.2 mole. 4-chlorobutyryl chloride28.2 g., 0.2 mole. Aluminum chloride, powdered 33.2 g., 0.25 mole.Carbon disulfide 300 ml.

The product obtained is extracted with ether and the ether extractwashed with water, dried over sodium sulfate, filtered and evaporated todryness on the steam bath. The residu is recrystallized 'from benzene togive 3- methyl-4-(4-chlor0butyryl)phenoxyacetic acid, M.P. 86.5 88 C.

Analysis.-Calculated for C H ClO C, 57.67; H, 5.59; Cl, 3.10. Found: C,57.52; H, 5.76; CI, 13.09.

Example 33.3-methyl-4-(4-plzenylmercaptobutyryl) plzenoxyacetic acid Asolution of 2.2 ml. of th'iophenol in ml. of ethanol containing 1. 12 g.of potassium hydroxide and 2.6 g. of4-(4-chlorobutyryl)-3-methylphenoxyacetic acid is heated on a steam bathfor 30 minutes, cooled and poured into m1. of water. The solution isacidified with hydrochloric acid and the resulting oil is extracted withether. The ethereal extract is washed with Water, dried over sodiumsulfate, filtered and evaporated to dryness. The residue isrecrystallized from carbon tetrachloride to give3-methyl-4-(4-phenylmercaptobutyryl)-phenoxyacetic acid, M.P. 60-62 C.

Analysis.-Calculated for C H O S: C, 66.20; H, 5.84. Found: C, 66.18; H,5.64.

Example 33-A.3-methyl-4-p-t0lylmercaptoacetylphenoxyacetic acid To acooled solution of 5.0 g. (0.02 m.) of p-methylthiophenol in ml. ofethanol and 8 ml. of 20% aque- Example 34.Etlzyl 3-metlzyl-4-[4-(4-m0rpholinyl) butyryl]pllenoxyacetate hydrochloride A solution of 3methyl-4-(4-chlorobutyryl)-phenoxyacetic acid (5.4 g., 0.02 mole)prepared as described in Example 32 and morpholine (8.7 g., 0.1 mole) in30 ml. of benzene and 50 mg. of potassium iodide, is heated under refluxfor 24 hours, filtered and concentrated to dryness in vacuo. The residueis heated under reflux for 2 hours with 50 ml. of 30% alcoholic hydrogenchloride and the solution concentrated to dryness in vacuo. Aqueoussodium bicarbonate is added and the mixture is extracted with ether. Theethereal extract is washed with water, dried over sodium sulfate,filtered and evaporated to dryness on a steam bath. The residue iscrystallized from alcoholic hydrogen chloride to give ethyl S-methyl- 174- [4- (4-morpholinyl) butyryl] phenoxyacetate hydrochloride, M.P.13l.5l34.5 C.

Analysis.-Calculated for C1 H2 ClNO C, 59.14; H, 7.31; N, 3.63. Found:C, 58.92; H, 7.24; N, 3.59.

Example 35 .2-(ichloro-l-batyrylphenoxy) ethoxyacetic acid Step A:Preparation of 2-(3-chloro-4-butyrylphen0xy) ethanl.3' chloro 4hydroxybutyrophenone 120.0 g., 0.604 mole) is added to a solution ofpotassium hydroxide (40.0 g., 0.604 mole) in absolute ethanol (250 m1.).Ethylene chlorohydrin (48.0 g., 0.604 mole) is added to the resultingyellow solution, and the solution placed in a glass lined autoclave andheated at 150 C. for 6 hours. The sodium chloride that forms is removed.by filtration and the filtrate evaporated at reduced pressure, pouredinto water (100 ml.) and extracted with ether. The ether extract iswashed with sodium hydroxide solution (three 60 ml. portions) and thenwith water and dried over sodium sulfate. The ether is removed byevaporation and the residue distilled, the fraction boiling at 156-170C. at 0.6 mm. pressure being collected to give 118.5 g. of 2-(3-chloro-4butyrylphenoxy)ethanol.

Step B: Preparation of 2-(3-chloro-4-butyrylphen0xy) ethoxyaceticacid.-To a mixture of sodium hydride .(53% in mineral oil; 5.92 g.,0.124 mole) in 1,2-dimethoxyethane (100 ml.) is added slowly2-(3-chloro-4- butyrylphenoxy)ethanol (30.0 g., 0.124 mole) in 1,2-dimethoxyethane (50 ml.). The mixture is stirred for /2 hour and ethylbromoacetate (20.6 g., 0.124'mole) then is added with stirring. Themixture is refluxed for 3 hours and the 1,2-dimethoxyethane then removedby evaporation. Sodium hydroxide (10.0 g., 0.25 mole) in water (50 ml.)is added to the residue and the mixture heated on a steam bath for 2.75hours. After cooling, the mineral oil is extracted with ether and theresidue is acidified with concentrated hydrochloric acid. The oil thatseparates is removed, Washed with water, dissolved in ether and.extracted With sodium bicarbonate solution. The sodium bicarbonatesolution then is acidified and the oil that forms is extracted withether, the ether extract separated and dried over sodium sulfate. Afterremoval of the ether by evaporation, the residue is distilled, thefraction boiling at 190260 C. at 0.5

pressure being collected to give 14.0 g. of 2-(3-chloro-'4-butyrylphenoxy)ethoxyacetic acid.

Example 35-A.-[2 (3-chloro-4-butyrylphenoxy) ethylthi01acetic acid StepA: Preparation of 2-(3-chloro-4-butyrylphen0xy) etlzylthio1aceticacid.'2 (3 chloro 4 butyrylphenol prepared as described in Example 35,Step A, is treated with thionyl chloride in pyridine solution to obtain2-'(3-chloro-4-butyrylphenoxy)ethyl chloride.

Step B: Preparation of [2-(3-chl0r0-4-butyrylphen0xy) ethylthi0]aceticacid.2 (3 chloro 4 butyrylphenoxy)ethyl chloride is heated with anaqueous alcoholic solution of one equivalent of mercaptoacetic acid andtwo equivalents of sodium hydroxide. Acidification of the reactionmixture precipitates [2-(3-chloro-4-butyrylphenoxy) ethylthio] aceticacid.

Example 36.3-metliyl-4-chl0r0acetylphenoxyacetic acid The above productis prepared following substantially the same process described inExample 22 using the following substances:

3-methylphenoxyacetic acid 33.3 g., 0.2 mole. Chloroacetyl chloride 22.6g., 0.2 mole. Aluminum chloride, powdered 80 g., 0.6 mole. Carbondisulfide 300 ml.

The solid product that forms is collected on the filter,

washed with water, air dried and recrystallized from benzene to give3-methyl-4-chloroacetylphenoxyacetic acid,

M.P. 11s-120 c.

Analysis.-Calculated for C H ClO C, 54.44; H,

4.57; Cl, 14.61. Found: C, 54.68; H, 4.66; Cl, 14.45.

Example 37-A.3-methyl-4-phenoxyacetylphenoxyacetic acid A solution of3-methyl-4-chloroacetylphenoxyacetic acid, from Example 36 (2.4 g., 0.01mole) and phenol (1.88 g.), in 50 ml. of Water'and 4 ml. of 20% aqueoussodium hydroxide is heated on the steam bath for 1 hour, cooled andacidified. The product obtained is crystallized from a mixture ofbenzene and petroleum ether to give3-methyl-4-phenoxyacetylphenoxyacetic acid, M.P. 145- 148 C.

Analysis.Calculated for C H O C, 68.08; H, 5.38. Found: C, 68.31; H,5.57.

Example 37B.3-methyl-4-benzylmercaptoacetylphenoxyacetic acid To asolution of 16.6 g. (0.1 mole) of 3-methylphenoxyacetic acid and 10.0 g.(0.1 mole) of succinic anhydride in ml. of carbon bisulfide and 50 ml.of nitrobenzene maintained at 30 C., 60 g. (0.44 mole) of aluminumchloride is added portionwise over a 30 minute period. The reactionmixture is allowed to stand at room temperature for 2-3 days. Thesolvent is decanted and residual solid is added to a mixture of ice andhydrochloric acid. The solid is collected on the filter, dissolved inbicarbonate solution and extracted with ether. The bicarbonate solutionis acidified and the product is recrytallized from water to give 16.5 g.of 3-methyl-4-(3-carboxypropionyl)phenoxyacetic acid, M.P. 163 C.

Analysis.Calculated for C H O C, 58.64; H, 5.30. Found: C, 58.40; H,5.33.

Other saturated acylphenoxyalkanoic acids (VII) and saturatedacylphenylmercaptoalkanoic acids prepared as intermediates in making thenovel compounds of this invention are identified in Tables II throughVI.

The products in Tables II and III are prepared following substantiallythe same procedure described in Example 22, with the exceptionequimolecular quantities of the phenoxyalkanoic (VI) orphenylmercaptoalkanoic acid (VIa) are substituted for the3-chlorophenoxyacetic acid employed in Example 22, and equimolecularquantities of the acyl halide, R CH COCl, identified in the tables aresubstituted for the propionyl chloride used in Example 22. In mostinstances the phenoxyalkanoic acid or the phenylmercaptoalkanoic acidused as a starting material was a known compound. In the few cases wherethis was not so, the example described the preparation of the prodnet isnoted in column 2 of each table. The end products (VII) are identifiedin each table by melting or boiling point and by elemental analysis forthose products that Were purified. It should be noted that the radicalsR R R R R and B in the starting materials (VI and VIa) are retainedunchanged in the end products (VII) and are identified in the tables.

TABLE II R R 4 R3 l l OBC 01H memo 001 A1013 cs. R CI'IZG OO-BCOH 5 VI RIt VII End product Prepn. phenoxy- Ex. acetie R R R R B R M.P. AnalysisNo. acid Yield, (B.P.

Ex. N0. percent 0.

Empirical C II Cl 38... Cl H H H CH2 CH3 69 147-148 CuH11C1O4Z C310-.-"54.44 4. 57 14. 6]. Found..- 54.64 4.79 14.43 39 H H H H CHz- CHaCHz- 66137-139 01211 4042 Cale..." 54.85 6.35 F0und 64.69 6.53 40 H F H H -CHz-CHaCHr- 67 131. 5-1335 Not purified 41- H C1 H H CH; CHaCHr- 51 89-90C1gH 3ClO C81C 56.15 5.10 13.81 Found 56.24 5.43 13. 57 42. C1 C1 H H-CH1 CHaCHr 77 110-111 C1gH1 C1gO4Z Oulc 49.51 4.15 24.36 Found 49.814.22 24.40 43 O1 11 Cl H CH2 CHaCHz- Not purified 44.. H Br H H CHzCHaCHz- 63 77-78 C12H1aB104) Cale 49.86 4.35 B1, 26.54 FOUI1(1 47. 944.49 Bl, 26.37 45." H I H H -CH: oHaoH'r- 30 86-87 (71212113104 Cale41.40 3. 76 I, 36.45 Found 41. 27 3. 92 I, 36.23 46... H CH3 H H H CH2-CHaCHz- 83 84-86 013111 042 C310--- 66.08 6.83 F0l1nd 67.03 6. 98 47 HCH3 H H CH2- CHsCHr- 65-665 013111 041 C21l0 66.08 6.83 Found. 65.42 7.09 48... CH3 CH3 H H -CHz- CH3CH2- 67 37-88 (31 1115042 C211 67. 18 7.25 67. 74 7. 27 49 CH3 H C113 H CH2 CH3CH3 I. S4 125. 8-127 67. 18 7. 2567. 50 7. 14 50 CH3 11 H CH3 CHg CHaCHr 63 119-120 67. 18 7. 25 67.037.29 CH3 CH H CHz CH3CH3 82 128-1295 68.16 7.63 67.98 7.42 CH H CH -CHgCHaCHz 109. 5-112 68.16 7.63 68. 15 7. 86 CH CH CH CHz CH3CH 29 143-145Not analyzed CH3 CH3 H CHg CH3CH 65 83-86 Calc 67.18 7.25 F0und 67.117.33 C 115 H H -CH CHaCHr- 64 0141113042 Calc 67.18 7.25 F0und 67.137.27 56". (CH3)zCH- H CH3 H -CHz CHaCHr- 96 -1015 C1sH22O4Z Calc 69.047.97 F0und 68.72 7.69 57 CH3 Cl H H -CHz- CH3(CHg)2. 94 91-915 C13H1C1O4:

Cale--. 57.67 5.59 F011I1C1 57.96 5.13 58-.- H C1 H H 'CH2 CHa(CH2)z- 3782.5-83.5 C1aH1 C1O C81 57.68 5.58 13.10 Found 57.71 5.43 12.87 59-.- HC1 H H -CH2 (CH3)2CH 107-108 01311150104:

Calc 57.68 5.58 13.10 F011J1d 57. 52 5.71 13.13 60 H C1 H H -CH2-CH3(CH2)3 18 88-89 C14H17C1O Ca1c 59.05 6.02 12.45 Found." 59.05 5.7612.20 61 H C1 H H CH2 CH3(CH2)4--- 27 102. 5-1035 C 5HwC1O4:

Ca1e 60.30 6.40 11.87 F01111d 60.60 6.52 11.78 2 H C1 H H -(CHz)2- CHa-40 -117 C I-1 C10 Cale. 56.15 5. 13 13. 81 Found 55.76 5.28 13.49 63". HC1 H H -(CH2)2- CH3CHz 58 82.5-84 C13H15C1042 Ca1c 57.67 5.58 13.10Found 57.52 5.78 13.10 64." 26 C1 CH3 H H CHz CHsCHr- 91 95-97 C 11 5ClOCale 57.67 5.58 Found--- 57.44 5.77 e 65... H CH H H -CHz-- CH- 20 91-93C14H 5F3O4! C316-.-" 55.26 4.97 F, 18.73 CH: Found." 55.50 4.91 I",18.67

TABLE IIOontinuel 4 3 4 a I I I l OBC 0211 R CH2COO1 +.A1Ol3 OS:R'-'CH2C O-QO-B-COzH I I I R IR VI R R VII End product Prepn. phenoxy-Ex. acetic R R R R B R M.P. Analysis No. ac Yield, (B.P.

Ex. No. percent C.

. Empirical C H 01 66... 1T 01 H H CH (CH:)2CHCHz- 26 89. -9001413120101:

Cale"--. 59.05 6.02 Found"- 58. 81 6. 08

67 H CL--- H H -CH;: H 43 107. 5-108. 5 CH11C1O4:

Oa1c 60.71 5.78 11.95 Found 60. 72 6. 01 11. 90

68. H Cl H Hg CHz 118-118. 5 (311111110104:

' Calc- 61. 83 6. 16 11. 41 61. 79 6. 36 11. 27 69--- FT OH; H CHg H180-182 63. 45 5. 81 63. 18 5. I-(CHQF b H CH2- CzHp- 116-118 68. 68 6.92 68. 49 6. 85 71--- H 01 H CH onl@ Not purified 72". H 01 H H (CH;);CH3. 31 91. 7-93 CrzHmClOq:

Calc 56.15 5.11 13.81 Found- 56. 51 5. 34 13. 69

B 197-199 at 012 mm. b 2,3-trimctl1ylene group.

TABLE III R R 34 Ba I I I I s B-o 02H memo 001 A101 cs, memo 0-QS-B-C0211 I I I I R R VIa R R VII End product Prepn. phe- Ex. noxymer- N o.capto R R R R B R Analysis acetic acid Yield, M.P., 0.

Ex. No. percent Empirical C H 01 CiiHuClOsS: 7% H 01 H H CH2 CH3 4489-91. 5 Cale 51.05 4. 29 51.02 4. 55

74 H CH H H CH: CH3- 37 93. 5-94. 5 60. 48 5. 92 60. 47 5. 84

75 21 H 01 H H (CH2)2- GHa- 36 73-75. 5 52. 84 4. 52. 83 5. 00

Additional saturated acylphenoxyacetic acids (VII) prepared asintermediates in making the novel compounds 70 of this invention areidentified in Table IV. The products identified in Table IV are preparedfollowing substantially the same reaction described in Example 23 withthe exception that the acylphenol (IV) identified in Table IV wassubstituted, in an equimolecular amount, for the 3-propio-. 75

nylphenol employed in Example 23. Column 2 identifies the example whichdescribes the preparation of the acylphenol employed in each example andthe saturated acylphenoxyacetic acid (VII) end products obtained areiden- TABLE IV R R R R I I I -on 13101120010111. NaH g g I -o cnlcozn R'CHQCO I R CH2CO R R R It IV VII End product Ex. Prcpn. of Position No.acylphenol R R R R of R Analysis Ex. No. R CH CO Yield, M.P.,C.

percent Empirical C II Cl 76---. 9 22-0111 3-Il 4-011 6-H 5 C: I5 5798.5-99.5 1-1180 Calc 67.18 7.25 Found 67.44 6.98 77---. 4 611 3CII1 4-HCHa 2 C7IT5 64 108-109 Notpurificd 78.... 5 6I-I 3C1 4H 5-01 2 c2II5- 7499-101 416 4:19 79"-- 3 6II 3H 4-H 5C1 2 CH1- "1185-1105 457 4:52 80.--.6 2CI 4-C1 5II 6H 3 C111 50 103-105 C zII 2ClzO I Calc 49.50 4.10 F0und49.02 4.30 81 7 2Cl 4I'I 5-H 6-11 3 C211; G2 74.5-76.5 01111110101:

Calc 50.15 5.10 Found 50.00 5.19 S2 8 6*11 3CII3 4-H 5H 2 C2135 61112.5114.5 0 31 1 50 06.08 6.83 Found, 60.28 0.84 S3 2II 3Cl 5-H 0I'I 4(CHs)aC 103-104 C HUCIQ Cale..- 59.04 6.01 12.31 Found 59.01 5.80 12.2884... 1 2Cl 3C1 5H 6-H 4 I H 76 127-128 (31 11 00 0 C2110 54.41 4.8721.42 Found"- 54.84 4.92 21.30 m. 18 2-01 3Cl 5-H 6-H 4 147-148CmILsClzOg Cale..-" 55.66 5.26 20.54 Found 50.25 5. 20.55 SG. 10 2-113-01 5-11 s11 4 G 7.0 117-118 omnnoiolz CaI0 61.83 6.16 11.41 Found.01.79 0.30 11.27

The saturated acylphenoxyalkanoic acids (VII) identified in Table V areprepared following substantially the same procedure described in Example24 With the exception an equimolecular quantity of the acyl-phen'ol (IV)identified in Table V is substituted for the 2'-chloro-4'-hycompound),and the acylphenoxyalkanoic acid (VII) end products obtained areidentified by melting point and elemental analysis. It should be notedthat the radicals, R R R R R and B in the starting materials areretained unchanged in the acylphenoxyalkanoic acid (VII)droxybutyrophenone used in Example 24, and an equiend products and areidentified in Table V.

TABLE V R4 R3 R4 I I I I B onic oQ-on 111110010211, CgH5ONa 11 01110OOBCO1H I R5 R6 IV R5 R5 VII End product Ex. Prepn. N0. acylphenol R R4R R B R2 Analysis EX. N0. Yield, M.P.,

percent 0.

Empirical C II Cl CmHiaNOa: 87 13 N01 CH H H -GH1 CzH5- 53 134-136 Calc55. 51 5. 37 N,4.9s Found. 55. 09 5. 25 N, 5. 00 CH I 015111801011 SS 10II C1 H H CH3CHCII3 C2H5 08-60 Calc 00.30 0.41 11.87 I Found 60.50 0.3211.71

016 20 4 S0 -(CH1)4 B H H CH2-- C2H5- 100-108 Calc 69. 54 7. 30 Found"09.28 7.19

11 End product is 2,3-tetramctliylene-4-butyrylphcnoxyacetic acid.Reaction was run in presence of sodium isopropoxide.

molecular quantity of the halocarboxylate, Br-BCO C H also identified inTable V is substituted for the ethyl a-bromobutyrate used in Example 24.Column 2 of the table identifies the example which describes thepreparation of. the acylphenol (IV) employed in each example (if noexample number is given, the acylphenol is a known 74'-hydroxybutyrophenone employed in Example 25.

tervals five or six times.

26 kept at a temperature between about 25 to 30 C. for 1 hour and thenboiled for 20 minutes, cooled, diluted with water and acidified withhydrochloric acid to yield 3-chloro 4 [2 phenyl 3 (1piperidyl)propionyl] phenoxyacetic acid hydrochloride.

Example 97.3-triflu0r0methyl-4-[Z-(dimethylaminomethyl)-butyryl]phenxyacetic acid hydrochloride Step A: Preparation of 3trz'fluoromethyl 4 bromophenyl allyl ether.3-trifluoromethyl 4bromophenol TABLE VI I ia Re I IV R i VII 7 End Product Prepn. Ex. acyl-Position of No. phenol R R R IN RZCHQCO R Analysis Ex.No. Yield, M.P.,

- percent "0.

Empirical C H 01 014 1 90 2-H 3-OCHzCOzH- 5-H 6-H 4 C H 54 159.2- Cale56.75 5.44

. 160 FOI1I1d 56.85 5.12

Cu 12Clz04Z 91"-- 11 2-H 3-01 5-01 6-H 4 CzH 65 112- Calc 49.51 4.1524.36

113 Found 49.94 4.31 24.10

C12H12B1C1O4: 92---- 12 2-Br 3-01 5-H 6-H 4 0;]1 42 105.5- Cale 42.953.60 Br, 23.81 I 107 Found 42.16 3.59 Br, 23. 76

93-.-. 14 2-H 3NHCOCH 5H 6-H 4 C2H5- 21 177- Not purified 94---. 16 2-Cl3Cl 5-H 6-H 4 (OH3)2CH 64 110.5- Calc 51.17 4.62 23.24 112 Penn 51.424.77 23.07 CnHw hO-fi 95---- 16 2-Cl 3Cl 5-H 0-H 4 (CH;) CHCH 67 108.5-Calc 52.68 5.05 22.22

109.5 Found 52.80 5.08 22.

Examples 96 through 184 which follow describe the preparation of novel,B-aminoacylphenoxyand ,B-aminoacylphenylmercapto derivatives ofmonocarboxylic acid compounds (VIII) of this invention. It should beunderstood that the products described below are representative of thenovel products of this invention and that the invention is not limitedto those compounds specifically described. The invention alsocontemplates the inclusion of other related compounds which fall withinthe scope of the disclosure and the appended claims.

Example 96.3-chl0ro-4-[Z-(dimethylamiriomethyl) butyryl] -phenoxyaceticacid hydrochloride In a 100 ml. round flask equipped with an outlet tubesuitable for application of intermittent suction, an intimate mixture of3 chloro 4 butyrylphenoxy- :acetic acid (from Example 38) 5.12 g., 0.02mole.

Paraformaldehyde 0.7 g., 0.022 mole. Dimethylamine hydrochloride 1.78g., 0.02 mole. Acetic acid 4 drops.

is heated on the steam bathfor about 1.5 hours during which time suctionis applied for about one minute in- Upon cooling, the product isisolated by triturating the reaction mixture with acetone. The whitesolid that forms is crystallized from acetonitrile and then fromisopropyl alcohol to give 3-chloro- 4- [2- (dimethylaminomethyl)butyryl] phenoxyacetic acid hydrochloride, M.P. 127-129 C.

'Analys is.Calculated for C H CINO 'HCI: C, 51.44; H, 6.04; Cl, 20.25.Found: C, 51.32; H, 5.90; Cl, 20.19.

Example 96A.3-chl0ro-'4-[Z-phenyl-3-(1-piperidyl)-propionylJp-henoxyacetic acid hydrochloride 3-chl0ro 4phenylacetylphenoxyacetic acid (3.04 g., 0.01 mole) (from Example 86)and piperidine (1.87 g., 0.022 mole) are dissolved in methanol ml.) and37% formaldehyde (1.5 ml.) is added. The mixture is (12.05 g., 0.05mole) in solution in methanol is added to a solution of potassiumhydroxide (2.81 g., 0.05 mole) in methanol (35 ml.). The solvent then isevaporated and the residue dissolved in glycol dimethyl ether (50 ml.).and the mixture then refluxed for 1 /2 hours. Potassium bromide isremoved by filtration and the solvent evaporated. The residuetrifluoromethyl 4 bromophenyl allyl ether, B.P. 78 C. at 1 mm. pressure.

Analysis.Calculated for C H BrF O:-'C, 42.73; H, 2.87. Found: C, 42.19;H, 3.21.

Step B: Preparation of 3-trifluor0methyl-4-(I-hydroxybutyl)phenyl allylether.-To magnesium turnings (2.60 g., 0.14 mole) in ether m1.) there isadded 3-trifiuoromethyl 4 bromophenyl allyl ether (20 g., 0.0712 mole).The reaction is initiated and kept in progress by the slow addition ofethylene bromide (12.4 g., 0.0712.mole). After the magnesium has beenconsumed, butyraldehyde (5.12 g., 0.0712 mole) is added, and the mixturerefluxed for 1 /2 hours. The reaction mixture then is hydrolyzed byadding it to a saturated solution of ammonium chloride. The product isextracted with ether, the ether extract dried over sodium sulfate andevaporated. The residue is distilled yielding 11 g. of an oil, B.P.70-102 C. (0.3 mm. pressure). The oil (7.92 g.) was placed on a 4 cm.column of alumina (350 g.) and eluted with benzene until theeflluentbenzene contains no solute. This effluent is discarded. Theproduct then is eluted with a mixture of benzene and ether (2: 1) andthen with a mixture of benzene and ether (1:2) until the eflluentcontains no solute. The combined :benzene-ether efiluents are combinedand evaporated yielding 5.5 g. of3-trifluoromethyl-4-(l-hydroxybutyl)phenyl allyl ether, N 1.4836.

Analysis.--Calculated fOl' C14H17F302Z C, H, 6.25; F, 20.78; Found: C,61.79; H, 6.26; F, 20.18.

Step C: Preparation of S-triflaoromethyl-4-butyrylphenyl allyl ether.Thecompound prepared in Step B Allyl bromide (6.05 g., 0.05 mole) is addedis distilled yielding 10.5 g. of 3-.

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The following examples describe the preparation of representativefieaminoacylphenoxybenzoic acid compounds that also come within thepurview of this invention. pounds are prepared by substantially the samemethod described in Example 96, the acylphenoxybenzoic acids which areused as intermediates in this step are prepared by methods which differfrom those used in the preparation of the acylphenoxyalkanoic acids.Methods adaptable to the preparation of acylphenoxybenzoic acids aredescribed in the following examples and can be employed in thepreparation of other compounds of this type which come within the scopeof this invention. These procedures generally can be adapted to preparethe corresponding acylphenylmercaptobenzoic acid compounds also.

Example 179. 4-{3-chloro-4-[Z-(dimethylaminomethyl)propionyl]-phen0xymethyl}benz0ic acid hydrochloride Step A: Preparationof ethyl 4-(3-chl0ra-4-propi0nylphenoxymethyl) benz0ate.3chloro-4-propionylphenol 18 g. (0.10 mole) is dissolved in 50 ml. ofanhydrous methanol. Clean sodium metal (1.85 g., 0.08 mole) is added inport-ions. Ethyl 4-chloromethyl benzoate (10 g., 0.05 mole) is addedwhen the sodium is dimolved. The reaction mixture then is refluxed 4hours, the mixture allowed .to cool and 100 ml. of water is added. Ihereaction mixture is extracted With ethyl ether, washed with 5% sodiumhydroxide and water and the organic phase dried and evaporated to give abrown oil which crystal lines on standing. After recrystallization fromethanol there is obtained 15 g.. (86%) of ethyl 4-(3-chloro-4-propionylphenoxymethyl)benzoate, M.P. 5860 C.

Analysis.--Calculated for C 'H O Cl: C, 65.71; H, 5.47. Found: C, 66.26;H, 5.55.

Step B: Preparation of 4-(3-ehl0r0-4-propionylphenojcymethyl )benzoicacid.-Ethyl 4-(3-chloro-4-propionylphenoxymethyl)benzoa.te (5 g., 0.015mole) in 5% sodium hydroxide solution (20 ml.) is heated with stirringon a steam bath for 3.5 hours. Upon cooling and with acidification withconcentrated hydrochloric acid a white solid is obtained, which afterrecrystallization from a mixture of ethanol and water gives 4.1 g. (90%)of 4(3-chloro- 4- propionylphenoxyrnethyl)ibenzoic acid, M.P. 1=5-3 155C.

Analysis.Calculated for C17H15O4CII C, 63.95; H, 4.70. Found: C, 64.18;H, 4.91.

Step C: Preparation of 4-{3-ehl0r0-4-[2 (dimethylaminomethyl)propz'onyl] phenoxymethyfibenzoic acid hydr0chl0ride.The above productis prepared following substantially the same procedure described inExample 96, except the materials listed below are heated at 120- 130 C.for A hour:

Dimethylamine hydrochloride 2.5 g., 0.032 mole.

Example 180.-4-{3-chlor0-4- [Z-(dimethylahzinomethyl)butyryl]phen0xymethyl}benz0ic acid hydrochloride Step A: Preparation of4-chl0r0methylbenz0nitrile.- p-Tolunitrile g., 0.854 mole) is placed ina 3-necked flask fitted with gas inlet-outlet tube, stirrer andthermometer. The stirring is started and the nitrile is heated to 130 C.Chlorine gas is passed into the liquid at a moderate rate, and thereaction activated by an incandescent lamp. The addition is continueduntil' the nitrile takes up 30 g. of the gas (about 2 hours). Thematerial is allowed to stand overnight in air whereupon a crystallinemass forms. This is washed twice with ethanol and dried in air.Concentration of the ethanol solution to half its volume gives 73.4 g.(57%) of 4- chloromethylbenzonitrile, M.P. 7577 C.

While the fi-aminoacylphenoxybenzoic acid com- Step B: Preparation of4-chloromethylbenzoic acid- 4-chloron1ethylbenzonitrile (25 g., 0.164mole) is refluxed and stirred with concentrated hydrochloric acid (500ml.) 14 hours. Upon cooling a solid is obtained which is removed byfiltration, dried in a desiccator to give 26.6 g. (94.5%) of4-chloromethylbenzoic acid, M.P. 202- 203" C.

Step C: Preparation of ethyl 4-chlor0methylbenzoate.--4-chloromethylbenzoic acid (26.6 g., 0.156 mole) is dissolved inabsolute ethanol (225 ml.) and heated to 60 C. in a four-necked flaskfitted with gas inlet tube, thermometer, stirrer, reflux condenser, anddrying tube. Stirring is started, and anhydrous hydrogen chloride gas ispassed in for 1 hour, the temperature being maintained at 50-60 C. Thesolution then is refluxed one hour, cooled and permitted to standovernight. The ethanol then is evaporated in vacuo, the residue taken upin ether, washed with sodium carbonate, dried and evaporated to an oilwhich distills at 91-93 C. at 0.6 mm. pressure to give 22.7 g. (74%) ofethyl-4-chloromethylbenzoate.

Step D.- Preparation of4-{3-chl0r0-4-[Z-(dimethylaminomethyl)butyryl]phenoxymethyl}benzoic acidhydrochloride.The above product is prepared following substantially thesame procedures described in Example 179, Steps A through C by (a)Replacing the phenol employed in Step A by an equimolecular amount of3-chloro-4-butyrylphenol and employing the other substances andprocedure used in Example .179, Step A, to prepare the ester which thenis hydrolyzed by the procedure described in Step B of Example 179 togive a 64% yield of 4-(3ch1oro-4-butyrylphenoxymethyl)benzoic acid, M.P.144l45 C.,

(b) The benzoic acid then is reacted with dimethylamine hydrochloride bythe method described in Step C of Example 179 to give4-{3-chloro-4-[2-dirnethylaminomethyl) butyryl]phenoxymethyl}benzoicacid hydrochloride.

Example 18I.-3-{3-cltl0ro-4-[2-(dimethylaminomethyl) butyryl]phenoxymethyl}benzoic acid hydrochloride Step A: Preparation of methyl3-(bromomethyl)benzoate.-3-methylbenzoyl chloride (105.5 g., 0.68 mole)is placed in a 4 necked flask fitted with stirrer, reflux condenser,drying tube, thermometer, and dropping funnel, and heated to 180 C.,stirring is started and the temperature maintained at 180. C., andbromine (110 g., 0.69 mole) is added dropwise over one hour. The mixtureis then stirred an additional 1.5 hours at 180 C. and finally cooled.With stirring maintained, methanol (67 ml.) is added to the mixturedropwise over one hour. The mixture then is distilled to give the pureproduct which crystallizes upon standing. There is thus obtained 79 g.

(50%) of methyl 3-(bromomethyl)benzoate, B.P. 136- 137 C. at 8 mm.pressure.

Step B: Preparation of3-{3-chlor0-4-[2-dimethyliaminomethyl)bittyryl]phenoxymethyl}benzoicacid hydr0chloride.The above product is prepared following substantiallythe same procedures described in Example 179, Steps A through C, by

(a) Replacing the phenol and the benzoate employed in Step A byequimolecular quantities of 3-chloro-4- butyrylphenol and methyl3-(bromomethyl)benzoate respectively gives a 40% yield of methyl3-(3-chloro-4- butyrylphenoxymethyl)benzoate, an oil which distills at220221 C., at 0.3 mm. pressure,

(b) Hydrolyzing this ester by the method described in Step-B of Example176 gives a 77% yield of 3-(3-ch10ro-4-butyrylphenoxymethyl)benzoicacid, M.P. 132- 133.5 C., and then(c) reacting the benzoic acid compound with dimethylamine hydrochlorideby the procedure described in Step C of Example 179 gives3-{3-chloro-4-[Z-dimethylaminomethyl)butyryl]phenoxymethyl}-benzoic acidhydrochloride.

40 Example 1 82 .--M ethyl 2-{3-chlor0-4- [2- (dimethylaminomethyl)-butyryl] phenoxymethyl}benz0ate hydrochloride Step A: Preparation ofmethyl 2-(bromomethyl)benzoate.2-methylbenzoyl chloride g., 0.845 mole)is placed in a four-necked flask fitted Wit-h stirrer, reflux condenser,drying tube, dropping funnel and thermometer, and heated to 185 C.Stirring is started and bromine (141 g., 0.882 mole) is added dropwiseover 1.5 hours. The solution is stirred an additional 1 hour at 180 C.and allowed to cool. Methanol (84.5 ml.) is added dropwise over 1.5hours and the dark solution obtained is taken up in ether and washedwith saturated sodium carbonate and water and dried. The ether isevaporated in vacuo without the application of heat to give 189 g. (95%)of methyl 2-(bromomethyl)benzoate.

Step B: Preparation of methyl 2 -'{3 chloro 4 [2(dimethylaminomethyl)butyryl]phenoxymethyl}benzoate hydrochloride-Theabove product is prepared following substantially the same proceduresdescribed in Example 179, Steps A and C, by

(a) Replacing the phenol and the benzoate employed in Step A byequimolecular amounts of 3-chloro-4-butyrylphenol and methyl2(bromomethyl)benzoate respectively to give a 75% yield of methyl2-(3-chloro-4- butyrylphenoxymethyl)benzoate, M.P. 82-83 C., and

(b) Reacting the ester with dimethylamine hydrochloride by the methoddescribed in Example 179, Step C, to give methyl 2 {3 chloro 4 [2(dimethylaminomethyl)butyryl] phenoxymethyl}-benzoate hydrochloride.

Example 183.4-{3-chlor0-4-[2-(dimethylaminomethyl)butyryl]phenoxy}benzoic acid hydrochloride Step A: Preparation of4'-(3-chlor0phenoxy)acetophen0ne.3-chlorophenol (16.2 g., 0.125 mole)and solid potassium hydroxide (8.3 g., 0.125 mole) are combined andheated to C. under aspirator vacuum for 2 hours. 4-bromoacetophenone (25g., 0.125 mole) and copper powder (0.2 g., as catalyst) are added andthe mixture heated to 190-200 C. for three hours. After cooling thereaction mixture is extracted with a mixture of ether and 5% sodiumhydroxide. The ether layer is separated, washed with 5% sodium hydroxideand water, dried andevaporated to an oil. The oil is distilled at ISO-C. at 0.5 mm. pressure and the product obtained redistilled at 162-164C. at 2 mm. pressure to give 9 g. (29%) of4'-(3-chlorophenoxy)acetophenone which in the form of its semicarbazonemelts at 165-1665 C.

Step B: Preparation of 4-(3-chlorophenoxy)benzoicacid.4-(3-chlorophenoxy)acetophenone (5 g., 0.020 mole) is suspended ina solution of potassium permanganate (9.75 g., 0.062 mole) in 10% sodiumhydroxide (40 ml.) and heated on the steam bath with stirring for threehours. The acetophenone dissolves and manganese dioxide precipitates.The excess permanganate is reduced with 30% hydrogen peroxide and themanganese dioxide removed by filtration. The clear solution obtained isacidified with concentrated hydrochloric acid to give a white solid,which after recrystallization from a mixture of ethanol and water yields4 g. (80%) of 4-(3-chlorophenoxy)benzoic acid, M.P. 135- 136 C.

Analysis-Calculated for C H O C1: C, 62.79; H, 3.65. Found: C, 62.65; H,3.79.

Step C: Preparation of methyl 4-(3-chl0rophenoxy)benzoate.4-(3-chlorophenoxy)benzoic acid (16 g., 0.065 mole) is refluxedin anhydrous methanol (100 ml.) with a trace of dry hydrogen chloridefor 24 hours. The volume of methanol is reduced to about 25 ml. andwater (100 ml.) added. The mixture is extracted with ether and washedwith saturated sodium bicarbonate and water, dried and evaporated to anoil. The oil is distilled to give a product boiling at 159162 C. at 0.1mm. pressure yielding 14 g. (84%) of methyl 4-(3-chlorophenoxy)benzoate.

10. A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT OF A COMPOUNDHAVING THE STRUCTURAL FORMULA
 26. A MEMBER SELECTED FROM THE GROUPCONSISTING OF A COMPOUND HAVING THE FORMULA: